Multiple myeloma (MM) remains incurable largely due to acquired resistance to currently available chemotherapies. A sub-population of cancer stem cells (CSCs) in MM has been established; these MM-CSCs display increased tumorigenic and self-renewal capabilities along with chemo-resistance to several MM agents. Bortezomib (BTZ, Velcade) is a frontline MM drug however BTZ resistance is a major clinical challenge. Recent literature suggests that CSCs frequently show fundamental differences in oxidative metabolism relative to normal stem cells. Therefore, redox chemotherapeutics that induce mitochondrial reactive oxygen species (ROS) production and/or inhibit antioxidant mechanisms could potentiate selective killing of CSCs and complement standard chemotherapy to improve cancer prognosis. Our preliminary results show that MM- CSCs exhibit lower steady-state levels of ROS relative to bulk MM cells. Combination of BTZ (a ROS-inducing drug) with mitochondrial-targeted decyl-triphenylphosphonium agent (dTPP) or with a pharmacological inhibitor of thioredoxin reductase (auranofin) resulted in selective clonogenic killing of MM-CSCs and not normal CD34+ hematopoietic stem/progenitor cells. The current proposal will determine the biochemical mechanism and provide preclinical validation on the combination of redox-directed chemotherapeutics (dTPP and auranofin) to enhance BTZ cytotoxicity in MM-CSCs. In vitro studies on role of redox dysregulation in selective sensitization of MM-CSCs will be done in MM cell lines and primary human MM samples. In vivo studies will utilize systemic MM models (adoptively transferred primary human samples in NOD/SCID/c-/- mice and 5TGM1 syngeneic model). The proposed studies will provide a strong rationale for developing combination strategies that will enable oxidative metabolic targeting and selective elimination of MM-CSCs with potential to inhibit MM relapses and improve therapeutic outcome of MM patients.